Revising rapid-onset dystonia-parkinsonism: Broadening indications for ATP1A3 testing

Abstract

Background and objectives: Rapid-onset dystonia-parkinsonism (RDP) is caused by mutations in the ATP1A3 gene, which codes for the α-3 subunit of the Na⁺ /K⁺ ATPase. It has been characterized by rapid-onset bulbar dysfunction, limb dystonia, bradykinesia, and a rostrocaudal spatial gradient of expression, usually after a physiologic trigger. We reexamined whether these features were in fact characteristic.

Methods: We characterized phenotypic variation within a cohort of 50 ATP1A3 mutation-positive individuals (carriers) and 44 mutation-negative family members (noncarriers). Potential participants were gathered through referral for clinical suspicion of RDP or alternating hemiplegia of childhood. Inclusion criteria were having a ATP1A3 mutation or being a family member of such an individual.

Results: We found RDP is underdiagnosed if only "characteristic" patients are tested. Rapid onset and bulbar predominance were not universally present in carriers. Among those with at least mild symptoms of dystonia, rostrocaudal severity gradient was rare (7%). Symptoms began focally but progressed to be generalized (51%) or multifocal (49%). Arm (41%) onset was most common. Arms and voice were typically most severely affected (48% and 44%, respectively). Triggers preceded onset in 77% of the participants. Rapid onset, dystonia, parkinsonism, bulbar symptoms, headaches, seizures, frontal impairment, and a history of mood disorder and a history of psychosis were more common in carriers. Approximately half of the proband mutations occurred de novo (56%).

Conclusions: Our findings suggest that patients should not be excluded from ATP1A3 testing because of slow onset, limb onset, absent family history, or onset in middle adulthood. RDP should be strongly considered in the differential for any bulbar dystonia. © 2019 International Parkinson and Movement Disorder Society.

Figure 1:. Protein structure of the ATP1A3 Na,K-ATPase.

The sodium-bound form of the ATP1A3 Na,K-ATPase is shown in ribbon view, with the backbone locations of mutated amino acids in green and yellow. Three mutations were in the stalk domain. Two mutations were in the membrane domain not far from the ions, and five were in the P (phosphorylation) domain, including the aspartate (yellow) in the active site that is phosphorylated and dephosphorylated during each cycle of ion transport.

Figure 2:. Subjects with ATP1A3 mutations show progression to diffuse involvement without a rostrocaudal gradient of severity.

Predominance of dystonia by body region at onset (Left) and at initial study visit in symptomatic carriers (Right). Dystonia at initial study visit is subdivided into variation in carrier severity scores at a given region, and the percentage of carriers with moderate dystonia or greater at a given region. Carriers showed diffuse involvement without a clear rostrocaudal gradient of dystonia severity at the initial study visit. Symptoms typically began focally in arms or mouth, but were diffuse by initial study visit. All regions were affected in at least 85% of carriers but were not equally affected. Subjects most often displayed significant (moderate to severe) dystonia in their arms (77%) or speech or swallowing (70%). Fewer subjects scored in the moderate to severe range with respect to their legs (65%) or face (51%). Dystonia severity was derived from BFMDRS scores. Further detail on gradient calculation methodology is given in Supplemental Methods.